Discriminating Cathinone Analogs

Mar 15 2010 Published by under Cathinone, Drug Abuse Science, Neuropharmacology

My Google news alert for MDMA, Ecstasy and the like has been turning up references to a cathinone analog called variously 4-methylmethcathinone (4-MMC), mephedrone (2-methylamino-1-p-tolylpropan-1-one), Meow-Meow, MMCAT and a few other things. There has been one fatality attributed* to 4-MMC that I can find and a few bits of seized-drug analysis confirming that the stuff is indeed being used. A quick scan over at PubMed finds little reported on the effects of this compound in animal models or in humans. I did, however, run across an article on other cathinone analog drugs that caught my attention.
ResearchBlogging.orgThe newpaper reports on 4-MMC coming out of the UK, for the most part, are experiencing the usual difficulty in characterizing the subjective properties of an analog of a stimulant class of drugs. This not dissimilar to the case of MDMA and relatives such as MDA, MDEA/MDE which are structurally similar to amphetamine and methamphetamine but convey subtly different subjective properties. This also gives me an opportunity to talk about an animal model used quite a bit in drug abuse studies: The drug-discrimination assay. The paper of interest is the following one.
Cathinone: an investigation of several N-alkyl and methylenedioxy-substituted analogs. Dal Cason TA, Young R, Glennon RA. Pharmacol Biochem Behav. 1997 Dec;58(4):1109-16. (DOI)

In this case, for example, the rats were trained to discriminate 1.0 d-amphetamine (d-AMP) from saline. The drug (or saline vehicle) was administered by intraperitoneal injection and then the animal was placed in the operant chamber and allowed to respond on two levers to produce a delivery of sweetened powdered milk. When d-AMP was administered before the session one lever produced reward and this became the drug-associated lever for that animal (left/right was balanced across the group). Presses on the other lever were rewarded under saline conditions. In contrast to the self-administration paradigm, the drug is the cue but not the reinforcer of the lever pressing,
The critical step in this assay is that responses on the levers in the first 2.5 minutes of the session did not produce any consequences. Animals were considered trained when they made over 80% of their responses during this test interval on the drug-appropriate lever after receiving 1.0 d-AMP and less than 20% on the drug-appropriate lever after receiving saline. Once trained, animals are challenged with either different doses of the training drug or different drugs entirely. The procedure is interpreted as giving an indication of how similar the subjective properties of a drug is to the training drug and how potent that drug is relative to the training drug.
In this paper, the authors investigated the subjective properties of several cathinone analog compounds including N-Monoethylcathinone (N-Et CAT), N-mono-n-propylcathinone (N-Pr CAT), and N,N-dimethylcathinone (Di Me CAT), 3,4-Methylenedioxycathinone (MDC) and 3,4-Methylenedioxymethcathinone (MDMC). I have taken the liberty of graphing the data provided in tabular form in the paper.
DalCason97-1.pngAs you can see in the graph, as you decrease the dose of the training drug, the rats are less and less likely to "report" that they have been given the active training drug. This is a classic feature of the assay. In terms of the cathinone analogs under investigation, four of them would substitute for the training drug if you pushed the dose high enough. Notice that in two cases the necessary dose was higher on a mg/kg basis than the training dose of d-AMP. In two other cases, the full-substitution dose was similar, but the dose to get approximately halfway there was higher. One compound (MDC) did not fully substitute for d-AMP; part of the reason for this is that beyond the graphed dose range, the animals were behaviorally disrupted- i.e., they didn't make more than 5 total responses (on either lever) in the initial test interval.
So cathinone analogs are producing subjective properties similar to amphetamine in many cases, all well and good. At this point you are screaming that sure, this procedure just asks the animal to report if it is intoxicated on a drug or not. Unfortunately I don't have the time or inclination to go through the arguments step by step so I'll refer you back to the drug-discrimination database for the moment.
I did want to highlight two papers from Goodwin and Baker (here, here) that took the modestly unusual step of training rats to discriminate d-AMP and MDMA from saline using a three-lever setup. The take home here is that by using this procedure you can get the rats to report d-AMP classic stimulant-like effects differently from serotonin-mediated classic hallucinogen effects. The data confirm in a rat model that MDMA does indeed share stimulant and hallucinogen-like properties**. (Man, I wish more people would use this three-lever procedure.)
DalCason97-2.pngReturning the Dal Cason paper, we see that they also conducted another study in which the rats were initially trained to discriminate 1.5 mg/kg MDMA from saline and then tested on the methylenedioxycathinone and methylenedioxymethcathinone compounds. In this case 77% MDMA-like responding was produced at only 2 mg/kg of MDC and the 93% considered full substitution at 2.25 mg/kg. In contrast MDC did not substitute fully for d-AMP, producing the most d-AMP-like responding of 58% at 2.75 mg/kg. The MDMC compound produced full substitution for MDMA at 2 mg/kg (98% MDMA-appropriate) and nearly full substitution (77%) at 1.75 mg/kg. This drug produced full substitution for d-AMP at 3 mg/kg and 69% drug-appropriate responding at 2.75 mg/kg. Although this between-groups procedure is not as elegant as the three-lever paradigm, still we have some evidence here for how subjective properties of several cathinone analogs shake out in a behaving animal.
I'm hoping a lab or two is busily working on 4-MMC so we can start getting some data on the behavioral pharmacological properties of this drug which appears to be gaining popularity in the UK at the moment. Does it seem like a classic stimulant? Does it confer subjective effects more like MDMA? And then what are the modes of toxicity? The fatality I mentioned may have been associated with hyponatremia which is not uncommon in MDMA-related fatalities.
*in combination with cannabis. Cue designer drug fans complaining how it can't be the entactogen/stimulant, it must be the known danger of...um, uh-oh.
**I can't help undercutting my attempt to get you to believe in drug-discrimination by pointing out this paper (also from the Glennon group) showing that MDMA-trained rats will report cocaine as MDMA-like but cocaine-trained rats do not fully generalize to MDMA. If it were easy it wouldn't be interesting...
DALCASON, T., YOUNG, R., & GLENNON, R. (1997). Cathinone: An Investigation of Several N-Alkyl and Methylenedioxy-Substituted Analogs Pharmacology Biochemistry and Behavior, 58 (4), 1109-1116 DOI: 10.1016/S0091-3057(97)00323-7

15 responses so far

  • Just started reading the post but you remind me that I got a lot of correspondence from the UK about MMC being a problem when we were discussing K2 Spice, the JWH compounds now illegal in Europe but still legal in the US.

  • I wonder if people would be ginning up and killing themselves with novel shit like this with unknown properties if well-studied and well-understood shit like MDMA were available in known pure doses?

  • DrugMonkey says:

    Yes, yes they would CPP. Perhaps not in quite the same numbers, but there are always going to be some drugonauts. You need to spend some time reading bluelight..

  • Scicurious says:

    OMG I am so thrilled that you just talked about drug discrimination. You make my day, DM. And that three lever choice test is indeed lovely. It would be interesting to see a three lever choice with varieties of pure serotonergics, as well as varying dopaminergic affinities, to see how the subjective effects change as dopamine and serotonin affinity ratios change.

  • Anonymous says:

    Some people want to know the discriminative stimulus properties of drugs, but the possibility of Bad Things makes them prefer an indirect approach. Bluelighters have the same curiosity, but don't worry so much about Bad Things.
    There's someone out there that wanted to know badly enough to be the first person in history to eat 2-methylamino-1-p-tolylpropan-1-one.

  • Synchronium says:

    Factors attributed to the explosive popularity of mephedrone ( from http://www.synchronium.net/2010/01/06/should-mephedrone-be-legal/ ):

    Mephedrone has achieved this unusual status thanks to a number of factors. Firstly, it’s an effective stimulant, which is more than can be said for ecstasy and cocaine these days; the former consisting mainly of disagreeable piperazines (due to their cheapness, and until recently, their legal status) rather than MDMA, and the latter being incredibly inpure. Next up is the lack of a comedown that would normally be experienced with other stimulants, especially for new users. This means people can keep taking it for days on end with little to no perceived negative effects. The other major contributor is the price – at around £10 a gram, it undercuts a great many of its illegal counterparts, while often being more effective, or at least more reliable. Other factors include (potentially inaccurate) purity measures, the ease of buying it from the comfort of your own home with a credit card, rather than handing over a fistful of crumpled notes to a typical drug dealer, and of course its legal status. Although the majority of users understand that legal doesn’t mean safe, the fact that you can’t be imprisoned alongside murderers, rapists and other violent criminals for possessing it is certainly a plus. Oh, and it’s psychologically addictive – it won’t kill you if you stop taking it, but you might be able to think of nothing else.

  • Lauren says:

    Is the death you are referring to the one of the student in Sweden? The UK papers this morning are reporting 2 deaths in which this drug has been implicated: http://news.bbc.co.uk/1/hi/uk/8571935.stm

  • DrugMonkey says:

    Thanks for the tip Lauren. Yes I was referring to the Swedish woman.
    I am going to be looking forward to the Drug Advisory Council report, wonder what science they've managed to dig up.

  • Lauren says:

    The UK media are advising everyone who has ever taken mephedrone to get straight to hospital. I work for a drugs helpline and we've been absolutely flooded with anxious callers who took the drug months ago and are now convinced they are going to die. As quoted in the times:
    Detective Chief Inspector Mark Oliver said: “We have information to suggest these deaths are linked to M-CAT. We would encourage anyone who may have taken the drug or knows somebody who has taken the drug to attend a local hospital as a matter of urgency.”
    Nice one guys.

  • DrugMonkey says:

    Oh FFS. I hate that. How hard is it to get out what is known about the mech of toxicity of cathinone, classic stimulants, MDMA, etc and specify that they mean *acute* use. Furthermore they could point to what to look for, at the very least based on these kids and the woman in Sweden.
    and furthermore to specify that long-lasting toxic effects may be present, but they do not very likely represent an acute risk of dropping dead in the absence of more drug taking..

  • Juan Knapp says:

    Drug discrimination??? This is not a big deal for me.
    Actually, this techniques study the abuse-related effects of psychoactive drugs in rats. Another contribution this will provide refined insights into the dynamic psychological mechanisms of both drug effects and behavior.
    Just take note, it contributes a lot!

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